Title
Diagnostic dilemma: progressive femoral lesion in a young woman
Clinical case detail
A 21-year-old Lithuanian-born woman presented with a 3-year history of progressive, severe right thigh pain. The pain was worse at the end of the day and exacerbated by prolonged standing or walking, despite regular paracetamol and ibuprofen, as well as PRN oxycodone. She did not have any associated rash, arthralgia, unintentional weight loss, or systemic features of infection. Her medical history is otherwise significant for a microprolactinoma diagnosed three years earlier on weekly Cabergoline, a benign tectal plate glioma, mild vitamin D deficiency and pityriasis versicolour. She was a smoker and worked as a beauty therapist. She did not have any previous fractures or any family history of bone disorders.
Laboratory and medical imaging findings
Plain film radiography demonstrated extensive cortical bone thickening of the right femoral shaft with no malignant ossification or cortical erosion. Magnetic resonance imaging showed abnormal bone marrow signal distal to this region. Bone scan revealed significantly increased uptake in the distal femur, consistent with abnormal osteoblastic activity.
Initial biochemistry revealed normal serum alkaline phosphatase, albumin-adjusted calcium and phosphate; low 1,25-dihydroxyvitamin D of 46 nmol/L; and elevated procollagen type 1 amino-terminal propeptide (P1NP) of 116 ug/L (normal range 15-90 ug/L) with normal C-telopeptide (CTX) of 341 ng/L (normal range 150-800 ng/L). Parathyroid hormone, serum protein electrophoresis, insulin-like growth factor-1 and anti-nuclear antibody testing were all within normal limits, as were c-reactive protein, erythrocyte sedimentation rate and tryptase levels. DEXA scan revealed bone mineral density of 1.090 g/cm2 with Z-score of +0.6 at the femoral neck, and 1.207 g/cm2 with Z-score of 0 at the lumbar spine.
CT-guided bone biopsy of the femoral lesion demonstrated only focal lymphocytic infiltrate with no evidence of malignancy, granulomas or plasma cells. Gram stain revealed no polymorphs or organisms and there was no growth on tissue culture. Repeat CT-guided biopsy showed benign trabecular osseous tissue with some architectural disorder and focal areas of degeneration with again no growth on culture.
Given ongoing pain and investigations suggestive of an osteoblastic lesion, a dose of 5mg intravenous zoledronic acid was administered. Despite reduction of bone turnover markers (P1NP 32 ug/L, CTX 185 ng/L), pain relief was only transient, with significant nocturnal pain returning after three months.
Repeat imaging twelve months post zoledronic acid revealed progression in size of the lesion with persistent periostitis and marrow oedema, and localised change in morphology, as well as a new site of increased activity on bone scan suspicious for sternoclavicular joint involvement. Repeat open biopsy of the femoral lesion demonstrated areas of osteosclerotic bone and patchy osteonecrosis.
A provisional diagnosis of a SAPHO-CRMO spectrum syndrome is considered.
Brief outline of the literature
SAPHO syndrome, named for its typical features of synovitis, acne, pustulosis, hyperostosis and osteitis, is a rare condition characterised by chronic, sterile inflammation of the bones, often with associated autoimmune and inflammatory conditions of the skin and joints, although this is not always present1. Chronic recurrent multifocal osteomyelitis (CRMO) is a similar condition with many shared features, although age of onset is typically in childhood as opposed to adulthood in SAPHO, and indeed both conditions may exist on the same spectrum of disease, although the exact relationship between the two is not fully understood2.
Clinical presentation of either condition typically involves unifocal or multifocal bone pain of insidious onset, most commonly affecting the metaphysis of the long bones of the legs, although any bone may be affected, and sternoclavicular joint involvement is also particularly common in SAPHO syndrome, as was suggested on bone scan in our patient1-2.
Disease course is variable, ranging from mild, intermittent episodes or flares of pain, to persistent and progressive inflammation, which may potentially lead to significant morbidity, including bone deformities, fractures, arthritis, and nerve entrapment syndromes3.
Initial evaluation typically demonstrates normal inflammatory markers and negative blood cultures, with bone turnover markers reflecting disease activity4. Plain film radiography may demonstrate lytic lesions, sclerosis, hyperostosis and periostitis at sites of disease, whilst magnetic resonance imaging reveals bone marrow oedema, and bone scintigraphy typically demonstrates increased osteoblastic activity, and frequently identifies extra sites of asymptomatic disease5.
Bone biopsy is often required to exclude malignancy, and commonly demonstrates a mixture of fibrosis and inflammation, however pathological findings are indistinguishable from infectious osteomyelitis6. Diagnosis therefore remains clinical, incorporating history, laboratory and imaging findings, and histology results if available, and whilst validated diagnostic criteria are currently lacking, multiple have been proposed7-8.
Whilst the exact pathogenesis of SAPHO syndrome and CRMO remains unknown, both conditions appear largely autoinflammatory, and most likely osteoclast-mediated9. Treatment options therefore include standard dose non-steroidal anti-inflammatory drugs (NSAIDs) as first line, with up to half of patients achieving clinical remission, defined as resolution of pain with or without resolution of activity on bone scan, within one year, whilst additional treatment options also include bisphosphonates, tumour necrosis factor (TNF) inhibitors, and disease-modifying anti-rheumatic drugs (DMARDs)10.
3-5 take home messages (dot points)
- SAPHO syndrome and CRMO are rare bone disorders characterised by sterile bone inflammation and fibrosis, with or without associated inflammatory conditions of the skin and joints.
- Diagnosis of SAPHO syndrome and CRMO is often delayed, likely due to a lack of awareness of these conditions as well as the absence of validated diagnostic criteria.
- Early diagnosis and treatment of SAPHO syndrome and CRMO is important as it may prevent or ameliorate disease complications.
- Further research is required to fully elucidate SAPHO syndrome and CRMO disease pathogenesis and optimal treatment options.